Fundamentally different roles of neuronal TNF receptors in CNS pathology: TNFR1 and IKKß promote microglial responses and tissue injury in demyelination while TNFR2 protects against excitotoxicity in mice.

BACKGROUND: During inflammatory demyelination, TNF receptor 1 (TNFR1) mediates detrimental proinflammatory effects of soluble TNF (solTNF), whereas TNFR2 mediates beneficial effects of transmembrane TNF (tmTNF) through oligodendroglia, microglia, and possibly other cell types. This model supports the use of selective inhibitors of solTNF/TNFR1 as anti-inflammatory drugs for central nervous system (CNS) diseases. A potential obstacle is the neuroprotective effect of solTNF pretreatment described in cultured neurons, but the relevance in vivo is unknown. METHODS: To address this question, we generated mice with neuron-specific depletion of TNFR1, TNFR2, or inhibitor of NF-κB kinase subunit ß (IKKß), a main downstream mediator of TNFR signaling, and applied experimental models of inflammatory demyelination and acute and preconditioning glutamate excitotoxicity. We also investigated the molecular and cellular requirements of solTNF neuroprotection by generating astrocyte-neuron co-cultures with different combinations of wild-type (WT) and TNF and TNFR knockout cells and measuring N-methyl-D-aspartate (NMDA) excitotoxicity in vitro. RESULTS: Neither neuronal TNFR1 nor TNFR2 protected mice during inflammatory demyelination. In fact, both neuronal TNFR1 and neuronal IKKß promoted microglial responses and tissue injury, and TNFR1 was further required for oligodendrocyte loss and axonal damage in cuprizone-induced demyelination. In contrast, neuronal TNFR2 increased preconditioning protection in a kainic acid (KA) excitotoxicity model in mice and limited hippocampal neuron death. The protective effects of neuronal TNFR2 observed in vivo were further investigated in vitro. As previously described, pretreatment of astrocyte-neuron co-cultures with solTNF (and therefore TNFR1) protected them against NMDA excitotoxicity. However, protection was dependent on astrocyte, not neuronal TNFR1, on astrocyte tmTNF-neuronal TNFR2 interactions, and was reproduced by a TNFR2 agonist. CONCLUSIONS: These results demonstrate that neuronal TNF receptors perform fundamentally different roles in CNS pathology in vivo, with neuronal TNFR1 and IKKß promoting microglial inflammation and neurotoxicity in demyelination, and neuronal TNFR2 mediating neuroprotection in excitotoxicity. They also reveal that previously described neuroprotective effects of solTNF against glutamate excitotoxicity in vitro are indirect and mediated via astrocyte tmTNF-neuron TNFR2 interactions. These results consolidate the concept that selective inhibition of solTNF/TNFR1 with maintenance of TNFR2 function would have combined anti-inflammatory and neuroprotective properties required for safe treatment of CNS diseases.

Breastfeeding Practices for COVID-19-Infected Mothers: A Systematic Review and Meta-Analysis.

(1) Background: The ongoing COVID-19 pandemic has led to an increasing number of women giving birth while also grappling with SARS-CoV-2. The objective of this review is to examine the possibility of transmission of the virus from mother to infant through breastfeeding, skin-to-skin contact, and rooming-in and to explore methods for managing COVID-19-positive mother-infant dyads. (2) Methods: A comprehensive search strategy was employed that covered pertinent studies from the Cochrane Library, PubMed Central, and Scopus databases. The Matrix Method and PRISMA guidelines were utilized by the researchers, with the search being updated until 20 December 2021, one year after the initial vaccine delivery. The inclusion criteria for the study involved articles published in English, those employing broad search terms, and those comprising full-text reviews. Additionally, the researchers required that the articles be published from December 2019 onwards. To further analyze the data, a meta-analysis was performed to estimate the rate of infant infection from mothers who engaged in breastfeeding, skin-to-skin contact, and rooming-in practices. (3) Results: Eighteen studies were analyzed in this review, with an infected infant rate of 2.8%. The maternal practices used in these studies ranged from direct separation of the infant to direct skin-to-skin contact, rooming-in, and exclusive breastfeeding. One study investigated the factors associated with positive test results in newborns and found that only the maternal social vulnerability index >90 was a significant predictor. The type of delivery, rooming-in, and the mother's symptom status were not associated with positive neonatal outcomes. (4) Conclusions: According to current data, the incidence of perinatal infection with SARS-CoV-2 is relatively low. It is advised that mothers adhere to several supportive care measures, including engaging in breastfeeding, skin-to-skin contact, and rooming-in. These measures ought to be complemented by diligent hand hygiene, the wearing of masks, and the cleansing of breasts solely when necessary.